Myristic Acid Increases Dihydroceramide Δ4‐Desaturase 1 (DES1) Activity in Cultured Rat Hepatocytes

Ezanno, Hélène; Bloch, J; Beauchamp, Erwan; Lagadic‐Gossmann, Dominique; Legrand, Philippe; Rioux, Vincent

doi:10.1007/s11745-011-3638-x

Cited by 13 publications

(7 citation statements)

References 52 publications

(77 reference statements)

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“…As is the case with b5R, DES1 is dually targeted to the ER and mitochondria, and it was shown that protein N -myristoylation favors to localization to the mitochondria [26]. In addition, it was also demonstrated that protein N -myristoylation positively affected the enzymatic activity of DES1 [25], [27].…”

Section: Introductionmentioning

confidence: 88%

Protein N-Myristoylation Plays a Critical Role in the Endoplasmic Reticulum Morphological Change Induced by Overexpression of Protein Lunapark, an Integral Membrane Protein of the Endoplasmic Reticulum

et al. 2013

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N-myristoylation of eukaryotic cellular proteins has been recognized as a modification that occurs mainly on cytoplasmic proteins. In this study, we examined the membrane localization, membrane integration, and intracellular localization of four recently identified human N-myristoylated proteins with predicted transmembrane domains. As a result, it was found that protein Lunapark, the human ortholog of yeast protein Lnp1p that has recently been found to be involved in network formation of the endoplasmic reticulum (ER), is an N-myristoylated polytopic integral membrane protein. Analysis of tumor necrosis factor-fusion proteins with each of the two putative transmembrane domains and their flanking regions of protein Lunapark revealed that transmembrane domain 1 and 2 functioned as type II signal anchor sequence and stop transfer sequence, respectively, and together generated a double-spanning integral membrane protein with an N-/C-terminal cytoplasmic orientation. Immunofluorescence staining of HEK293T cells transfected with a cDNA encoding protein Lunapark tagged with FLAG-tag at its C-terminus revealed that overexpressed protein Lunapark localized mainly to the peripheral ER and induced the formation of large polygonal tubular structures. Morphological changes in the ER induced by overexpressed protein Lunapark were significantly inhibited by the inhibition of protein N-myristoylation by means of replacing Gly2 with Ala. These results indicated that protein N-myristoylation plays a critical role in the ER morphological change induced by overexpression of protein Lunapark.

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Section: Introductionmentioning

confidence: 88%

Protein N-Myristoylation Plays a Critical Role in the Endoplasmic Reticulum Morphological Change Induced by Overexpression of Protein Lunapark, an Integral Membrane Protein of the Endoplasmic Reticulum

et al. 2013

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“…on DES1/DES2 activity or expression. A body of evidence also suggests a role for DES1 myristoylation in the control of activity (44,79,80).…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Dihydroceramides: From Bit Players to Lead Actors

Siddique¹,

Chaurasia

et al. 2015

Journal of Biological Chemistry

119

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Sphingolipid synthesis involves a highly conserved biosynthetic pathway that produces fundamental precursors of complex sphingolipids. The final reaction involves the insertion of a double bond into dihydroceramides to generate the more abundant ceramides, which are converted to sphingomyelins and glucosylceramides/gangliosides by the addition of polar head groups. Although ceramides have long been known to mediate cellular stress responses, the dihydroceramides that are transiently produced during de novo sphingolipid synthesis were deemed inert. Evidence published in the last few years suggests that these dihydroceramides accumulate to a far greater extent in tissues than previously thought. Moreover, they have biological functions that are distinct and non-overlapping with those of the more prevalent ceramides. Roles are being uncovered in autophagy, hypoxia, and cellular proliferation, and the lipids are now implicated in the etiology, treatment, and/or diagnosis of diabetes, cancer, ischemia/ reperfusion injury, and neurodegenerative diseases. This minireview summarizes recent findings on this emerging class of bioactive lipids.

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“…Although the initial steps and the majority of de novo ceramide formation clearly take place in the ER ( 7,8 ), the enzymes involved in the fi nal steps of ceramide formation (CerS and dihydroceramide desaturase) were also found in mitochondria ( 14,84,85 ). Moreover, Ardail and colleagues provided evidence that MAM, the specialized ER compartment involved in the transfer of lipids and Ca 2+ between the ER and mitochondria (86)(87)(88), contains glucosylceramide and lactosylceramide synthases which tunnel glycosphingolipids to mitochondria ( 89 ).…”

Section: Lactosylceramide Suppresses Mitochondrial Respiration and Dementioning

confidence: 99%

Lactosylceramide contributes to mitochondrial dysfunction in diabetes

Novgorodov

Riley

et al. 2016

Journal of Lipid Research

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This article is available online at http://www.jlr.orgCompelling epidemiological and clinical data indicate that diabetes mellitus increases the risk for cardiac dysfunction and heart failure independently of other risk factors, such as coronary disease and hypertension. Lipotoxicity is an important contributor to cardiac dysfunction in both type 1 ( 1, 2 ) and type 2 ( 3-6 ) diabetes, which are characterized by excessive accumulation of triacylglycerols, long-chain acyl-CoAs, diacylglycerols, and ceramides in myocardium. Correlation of the increased ceramide level with development of diabetic cardiomyopathy has attracted special attention in recent years because of the well-documented ability of this sphingolipid to regulate a number of cell processes, including cell proliferation, growth arrest, differentiation and apoptosis, and the mediation of responses to stress stimuli .Ceramide is a hub of sphingolipid metabolism ( 7,8 ). The balance between ceramide-producing pathways and pathways that consume it dictates ceramide level in the cell. The de novo ceramide biosynthesis pathway, one of the major ceramide producing pathways, localizes in the endoplasmic reticulum (ER) and starts with the condensation of serine and palmitoyl-CoA producing 3-ketosphingonine, which, in turn, is rapidly converted to dihydrosphingosine. Subsequent acylation of dihydrosphingosine by a set of (dihydro)ceramide synthases (CerSs) gives rise to dihydroceramide. Finally, the removal of two hydrogens from the fatty acid chain of dihydroceramide by desaturase leads to the formation of ceramide. Other possible contributors to elevated ceramide level are: hydrolysis of SM catalyzed by SMases, Abstract Sphingolipids have been implicated as key mediators of cell-stress responses and effectors of mitochondrial function. To investigate potential mechanisms underlying mitochondrial dysfunction, an important contributor to diabetic cardiomyopathy, we examined alterations of cardiac sphingolipid metabolism in a mouse with streptozotocininduced type 1 diabetes. Diabetes increased expression of desaturase 1, (dihydro)ceramide synthase (CerS)2, serine palmitoyl transferase 1, and the rate of ceramide formation by mitochondria-resident CerSs, indicating an activation of ceramide biosynthesis. However, the lack of an increase in mitochondrial ceramide suggests concomitant upregulation of ceramide-metabolizing pathways. Elevated levels of lactosylceramide, one of the initial products in the formation of glycosphingolipids were accompanied with decreased respiration and calcium retention capacity (CRC) in mitochondria from diabetic heart tissue. In baseline mitochondria, lactosylceramide potently suppressed state 3 respiration and decreased CRC, suggesting lactosylceramide as the primary sphingolipid responsible for mitochondrial defects in diabetic hearts. Moreover, knocking down the neutral ceramidase (NCDase) resulted in an increase in lactosylceramide level, suggesting a crosstalk between glucosylceramide synthase-and NCDase-mediated ceramide utiliz...

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Myristic Acid Increases Dihydroceramide Δ4‐Desaturase 1 (DES1) Activity in Cultured Rat Hepatocytes

Cited by 13 publications

References 52 publications

Protein N-Myristoylation Plays a Critical Role in the Endoplasmic Reticulum Morphological Change Induced by Overexpression of Protein Lunapark, an Integral Membrane Protein of the Endoplasmic Reticulum

Protein N-Myristoylation Plays a Critical Role in the Endoplasmic Reticulum Morphological Change Induced by Overexpression of Protein Lunapark, an Integral Membrane Protein of the Endoplasmic Reticulum

Dihydroceramides: From Bit Players to Lead Actors

Lactosylceramide contributes to mitochondrial dysfunction in diabetes

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